Schizophrenia (SZ) is one of the most disabling mental illnesses. It also is associated with higher medical comorbidity and a 20- to 25-year shorter life span than the general population. There is indirect evidence suggesting that biological aging may be accelerated in SZ; however, this will be the first study of laboratory-based systemic and neurophysiological markers of biological aging comparing persons with SZ to normal subjects during critical periods of the adult lifespan (26-65 years). The study will use a selected panel of systemic biomarkers that track biological aging and may reflect the pathophysiology of aging, especially in SZ, in terms of insulin dysregulation (Homeostatic Model Assessment of Insulin Resistance), inflammation (C-reactive protein), oxidative stress (F2-isoprostanes), and cell aging (telomere length), as well as a validated EEG-based marker of neurophysiological aging (mismatch negativity) that is deficient in SZ patients, has robust associations with both aging and functional outcome, and serves as an intermediate phenotype in genomic association studies. Subjects will include 140 with SZ and 120 normal comparison subjects (NCs) aged 26-65 years. We will recruit more SZ than NC subjects because of expected greater variation in outcomes in the SZ sample, and to maximize power in analyses of illness- and treatment-specific variables in the SZ group. Subjects in each decade (26-35, 36-45, etc.) will be followed annually for up to four years in a Multi-cohort Longitudinal Design, a significant improvement over cross-sectional designs, with balanced recruitment providing 35 subjects with SZ and 30 NCs per decade. While age will be treated primarily as a continuous (if potentially nonlinear) predictor in the hypotheses, age cohort will be entered in preliminary analyses to estimate and test for the possible presence of significant age cohort and/or sampling (e.g., healthy survivor) effects. Baseline values and rates of change in these measures over time in the NC and SZ groups will be compared, after controlling for chronological age. We will examine the extent to which person-related factors such as perceived stress, smoking status, drug use, cognitive function, and physical activity patterns predict individual variation in biomarkers of aging in SZ and NC groups; and whether additional illness- and treatment-related factors (age of onset of illness, current and cumulative antipsychotic use) predict variation in those markers in the SZ sample. A secondary aim of the study will be to examine if everyday functioning is predicted by individual differences in biomarkers of aging. This project is related to the NIMH Strategic Objective # 2: charting mental illness trajectories to determine when, where, and how to intervene. This study is novel in its focus on biological aging in SZ and on putative explanatory variables of this process. Discovering whether accelerated biological aging occurs in SZ and understanding the underlying mechanisms should lead to new ways of predicting, tracking, and treating the serious medical co-morbidities commonly seen in this population. PUBLIC HEALTH RELEVANCE: Schizophrenia is one of the most serious and disabling mental illnesses, and is associated with a greater risk of physical diseases and higher mortality rates and there some indirect evidence suggesting that biological aging may be accelerated in schizophrenia. The goals of this study are to determine if there is more rapid biological aging in schizophrenia, using specific laboratory-based biomarkers, and to assess their relationship with functional outcomes on one hand and behavioral as well as disease- and treatment-related risk factors on the other. Understanding potentially malleable risk and protective factors for biological aging at an individual level may lead to development of new preventive and therapeutic interventions aimed at reducing the excess medical comorbidity and mortality in SZ.